Transforming growth factor beta (TGF() promotes epithelial differentiation and inhibits cell growth. Defects in TGF( signaling are common in cancer and frequently associated with reduced apoptosis and more aggressive tumor behavior. Though many TGF( signaling components function as tumor suppressors in breast, colon, and skin cancers, TGF( signaling in lung cancer is largely unexplored. My hypotheses are that defective TGF( signaling promotes tumor growth in LSCC and that specific TGF( signaling defects are associated with distinct clinical tumor behavior and distinct tracheal epithelial cell behavior. I have observed frequent loss of TGF( signaling molecules in human LSCC samples. In Aim 1 I will define the spectrum and consequences of TGF( signaling defects in human LSCC. In Aim 2 I will use cultured tracheal epithelial cells to determine the effect of specific TGF( signaling defects on apoptosis, cell cycle arrest, migration, and endogenous TGF( production. In Aim 3 I will create a novel mouse model of LSCC to examine TGF( signaling in vivo. In summary, these studies examine how TGF( signaling defects modulate behavior of airway epithelial cells in vivo and in vitro and how these changes promote the growth of LSCC.